Many activities of the human body involve the contraction of muscles. For instance, movement of the limbs, breathing activity, etc. The most complex and vital muscular activity of the human body is that of the heart, which functions as a pump and which, by contracting at the required times and in the required manner, controls the flow of blood throughout the body.
The heart is composed of different parts, which contract differently and with different timing, in order to permit the aforementioned pumping activity. The contraction of the heart is controlled by electric stimuli, which are generated at the cellular level by chemical reaction. However, it is well known in the art to control the timing of the contraction of the cardiac muscle, by the action of externally applied electric stimuli, through the so-called "pace maker".
In a copending PCT patent application No. PCT/IL97/00012, filed Jan. 8, 1997 by the same applicants herein, the specification of which is incorporated herein by reference, there is described a method and apparatus for modifying the force contraction of at least a portion of a heart chamber, which comprises applying a non-excitatory electric field, for a predetermined period of time, at a delay after activation, which causes the force of contraction to be increased. Substantial increases in the force of contraction are obtained, typically--but non-limitatively--in the order of 5%-50%. This increase in cardiac output is useful in order to obviate cardiac insufficiency due to a variety of pathological situations, e.g., the reduction of cardiac output due to the implantation of a pace maker, the insufficiency due to the results of the malfunctioning of a portion of the cardiac muscle, etc.
In another copending PCT/IL patent application, entitled "Apparatus and Method for Controlling the Contractility of Muscles", filed by the same applicants herein on the same day as the present application and identified as Attorney's Docket 4224/WO/97, the specification of which is incorporated herein by reference, there is described a method and apparatus for decreasing the force contraction of at least a portion of a heart chamber, which comprises applying a non-excitatory electric field of a polarity inverse of that required for obtaining an increase of muscle contractility, for a predetermined period of time, at a delay after activation, which causes the force of contraction to be decreased. The ability of reducing the contractility is of importance in a variety of situations, e.g., during surgery or as an aid in healing of hibernated areas of a heart after myocardial infarct.
Several severe diseases of the cardiac muscle cannot be treated effectively without the aid of drugs. However, many drugs used in therapy have a deleterious, side-effect in that they reduce the contractility and cardiac output of the heart and may cause life threatening arrhythmias. Some illustrative examples of drugs used in the treatment of congestive heart failure (CHE) are given below.
Congestive heart failure (CHF) is a complex clinical syndrome characterized by impaired ventricular performance, exercise intolerance, a high incidence of ventricular arrhythmias, and shortened life expectancy. Virtually all forms of heart disease can lead to heart failure, with coronary artery disease, hypertension, and diabetes mellitus being the most common in the U.S.
CHF can be broadly subdivided into two distinct forms (although several other classification schemes have been used). Distinguishing between the two forms is often difficult: 1. Diastolic dysfunction or diastolic heart failure; and 2. Systolic dysfunction or systolic CHF.
Changes in the structure and biochemical properties of the myocardium and peripheral vasculature occur during the development of CHF and these changes can contribute to further impairment of cardiovascular function. Many different drugs are used in the therapy of CHF, which affect the cardiac muscle, whether directly or indirectly, by causing changes in the cardiovascular system.
Recent studies indicate that metoprolol, a commonly used beta-blocker which can cause up-regulation of beta-1 receptors, can restore catecholamine responsiveness to patients with dilated cardiomyopathy.
Captopril, an ACE inhibitor that is commonly used to treat heart failure, has been shown to increase lymphocyte Gs and increase myocardial beta-1 receptor density.
Digitalis (cardiac glycosides): has been used clinically for over 200 years to treat heart failure and edema (dropsy), but its present use in treating CHF is controversial. Digoxin is the most widely used preparation of digitalis (half-life=1-2 days), although digitoxin (half-life=7 days) is also used in situations where long half-life may be an advantage.
However, Digoxin may be toxic at relatively low dosages, since it may cause arrhythmia and conduction problems, but the art has so far failed to provide means by which the desirable therapeutic effect of Digoxin or similar drugs may be maintained at low dosages, so as to avoid toxicity problems.
Beta-Adrenergic agonists: beta1-adrenergic agonists (dopamine, dobutamine, prenalterol, xamoterol) have been used to treat acute and chronic heart failure, but have limited usefulness in chronic CHF because of their arrhythmogenic effects, short duration of action, the development of tolerance, and necessity of parenteral administration.
Dobutamine is a moderately selective beta1-adrenergic agonist that lacks vasoconstrictor activity and causes minimal changes in heart rate. It is frequently added to nitroprusside when blood pressure is adequate to increase cardiac output.
Prenalterol and xamoterol are partial beta1-adrenergic agonists that may simultaneously stimulate beta1-receptors and block the receptors from stimulation by endogenous catecholamines, thereby protecting against beta1-receptor down-regulation.
Cyclic nucleotide phosphodiesterase (PDE-III, cGMP-inhibitable PDE) inhibitors: There are several agents that increase myocardial and vascular smooth muscle cAMP through inhibition of cyclic nucleotide phosphodiesterase PDE-III, cGI PDE) activity. These agents should therefore simultaneously increase cardiac output and reduce afterload.
The bipyridines, amrinone and mirinone, are potent PDE-III inhibitors that can be given orally or parenterally. They can be given orally, are generally well-tolerated, but can have significant non-cardiac side-effects (nausea, vomiting, thrombocytopenia).
Ca.sup.+ Channel Blockers: Ca.sup.+ channel antagonists are widely used in many types of heart diseases, including cardiac insufficiency, and cause direct arterial vasodilatation by the inhibition of Ca.sup.+ current. Ditiazem and Verapamil exhibit negative inotropic, chronotropic and dromotropic effect on cardiac function. Some of these drugs, such as Verapamin, have life threatening side effects, such as altering the A-V node conduction.
Anti-Arrhythmic Drugs: In cardiac insufficiency, and in other ischemic diseases, many patients suffer from arrhythmia. Drugs acting on the chronicity are known to cause many side effects.
It is therefore clear that it is highly desirable to be able to reduce the dosage of such drugs, whenever possible, or to obviate side effects and problems which they may cause.
It has now been surprisingly found, and this is an object of the present invention, that it is possible to obviate the aforementioned drawbacks of drugs used in the therapy of heart diseases, by applying a non-excitatory signal of the type described above, which increases the contractility of the cardiac muscle and its output. It has further been found that this can be achieved without generating adverse effects and/or without adversely affecting the activity of the drug which is administered to the patient.
It is an object of the invention to provide apparatus for the combined drug/electric-stimulation treatment, which can be used as a treatment aid for a patient in need of a medicine which impairs heart muscle contractility.
It is another object of the invention to provide a method for treating a patient in need of a drug which may impair the contractility of the heart muscle.
It is yet another object of the invention to provide apparatus useful in therapy, by means of which the dosage of drugs having potentially harmful side effects can be reduced or, alternatively, by means of which the dosage can be increased while keeping side effects within an acceptable range.
It is still another object of the invention to provide apparatus which cooperates with such drugs, its activity being related to the amount of the drug present at a given time in the patient's blood.
Other objects and advantages of the invention will become apparent as the description proceeds.